PROJECT SUMMARY (PROJECT 3, Project Leader: Graybiel, Massachusetts Institute of Technology) Our goal is to identify neural circuit mechanisms underlying major depressive disorder (MDD) and anxiety disorders to advance therapeutic treatments. Project 3?s Aims, coordinated with those of the other Projects, will capitalize on our findings on the physiology and function of the anterior cingulate cortex (ACC), strongly linked to MDD and anxiety disorders, and its connections with specialized neurochemical compartments of the striatum called striosomes. Striosomes are richly interconnected with the neuromodulatory dopamine system, a key site influencing motivational states and, in dysfunction, neuropsychiatric illness. We developed a non-human primate (NHP) version of the approach-avoidance (Ap-Av) task used in humans to study anxiety and depression, as well as rodent models allowing manipulation of the ACC-striatal circuit. We found that manipulation of this circuit can profoundly bias Ap-Av decisions, increasing avoidance behavior, and such effects can be mimicked by chronic stress, dose-dependently reversed by anxiolytics in NHPs, and induced by ACC-striosomal circuit manipulations in rodents. We now propose to determine the influence of nociceptin receptors (NOPR) on this circuit. Antagonists of NOPR given systemically increase striatal dopamine efflux, and this treatment reduces depression- and anxiety-related measures in rodent models and has shown initial promising findings in MDD. Notably, we recently found together with Project 4 that the nociceptin peptide, nociceptin/orphanin FQ (N/OFQ) is expressed selectively in striosomal neurons, neurons we recently demonstrated project directly to nigral dopamine neurons. Thus, we hypothesize that NOPR antagonists interrupt striosomal N/OFQ signaling at dopamine neurons modulating striatal dopamine release and biasing Ap-Av decision-making when individuals face cost-benefit tradeoffs. Aim 1 tests the hypothesis that NOPR antagonists can normalize a shift in Ap-Av behavior as well as neural striosomal and dopamine signals induced in mice by prior chronic stress. Aim 2 tests whether NOPR antagonists shift Ap-Av decision boundaries and neural activity by asking whether NOPR antagonists remain effective in the absence of striosomal N/OFQ, nigral NOPRs or both. Aim 3, importantly, will coordinately test NOPR effects in NHPs with recordings and microstimulation in the ACC during Ap-Av decisions. Contribution to Overall Center Goals and Interactions with Other Center Components. These Aims will provide a fundamental infrastructure for designing approaches to the treatment of MDD and anxiety disorders, a goal directly related to the other projects and the NIMH mission to understand, prevent and cure mental illness. We will establish a crucial behavioral bridge connecting mouse, NHP and human behavioral studies, including widely used mouse behavioral assays of anhedonia and avolition (Project 4), NHP Ap-Av behavior (our Project 3) and human Ap-Av behavior (Projects 1 and 2), in coordination with the Computational Core, to identify conserved behavioral and neural features across a translational panel of species.